1. Field of the Invention
The present invention relates to a cyclooxygenase-2 inhibitor. The inhibitor inhibits synthesis of prostaglandin H and I, or synthesis of their subsequent metabolites thromboxanes, and can be used as a drug for both treatment and prevention of ischemic diseases, senile dementia, cancer, asthma, arterial sclerosis, and various inflammation diseases.
2. Background Art
Cyclooxygenase (prostaglandin-endoperoxide synthase) is an enzyme that catalyzes in vivo synthesis of prostaglandin H2 from its substrate arachidonic acid. Prostaglandin H2 is physiologically very active. From prostaglandin H2, there are produced metabolites of prostaglandin D2, E2, and F2 and metabolites of thromboxane A2 and B2, all of which are also physiologically very active.
Consequently, inhibition of the cyclooxygenase activity results in inhibition of synthesis of these metabolites. Thus, the prostaglandin H2 inhibitors can inhibit not only prostaglandin H2, but also other physiologically very active compounds, such as prostaglandin D2, E2, and F2 and thromboxane A2 and B2.
Cyclooxygenase is widely known to be involved in inflammation. For treatment of such inflammation, various cyclooxygenase inhibitors have been widely used, including aspirin and indomethacin. However, at the time when these drugs were discovered, there was known only one type of cyclooxygenase that is ubiquitously present in the living body.
Another type of cyclooxygenase; namely, the inducible type of cyclooxygenase, has recently been discovered. This inducible type of cyclooxygenase is induced upon various stimuli and is called cyclooxygenase 2, whereas the ubiquitous type is now called cyclooxygenase 1. Furthermore, it has recently become clear that cyclooxygenase 2 is deeply involved in ischemic diseases, senile dementia, cancer, asthma, arterial sclerosis, and a variety of inflammation diseases. From these observations, cyclooxygenase-2-inhibitors are considered to be potentially very effective drugs for treatment of these diseases (G. Cirino. Biochem. Pharmacol. 55: 105-111, 1998).
In view of the foregoing, the present invention is to provide a pharmaceutical containing, as an active ingredient thereof, a compound which inhibits cyclooxygenase 2 to thereby serve as an excellent therapeutic drug for the abovementioned diseases, and which has low toxicity that causes only minor side effects to the extent that they are suitable for clinical use.
Accordingly, the present invention provides the following.
1) A cyclooxygenase-2-inhibitor comprising, as an active ingredient, a compound represented by the following formula (1) or (1xe2x80x2): 
wherein R1 represents a hydrogen atom or an alkyl group having 1-3 carbon atoms; R2 represents a peptide or protein capable of binding through its own thiol group within the molecule, or R1 and R2 may join to each other to form a single bond; and R3 represents a hydrogen atom, a halogen atom, an alkyl group having 1-3 carbon atoms, an alkoxyl group having 1-3 carbon atoms, a trifluoromethyl group, or a nitro group; and each of R4 and R5, which may be identical to or different from each other, represents a hydrogen atom, a halogen atom, an alkoxyl group having 1-4 carbon atoms, a trifluoromethyl group, or R4 and R5 may join to each other to form a methylenedioxy group; a salt thereof, or a hydrate thereof.
2) A cyclooxygenase-2-inhibitor containing, as an active ingredient, 2-phenyl-1,2-benzisoselenazol-3(2H)-one (hereinafter referred to as compound A), a salt thereof, or a hydrate thereof.
3) A cyclooxygenase-2-inhibitor comprising, as an active ingredient, a compound represented by the following formula (2): 
wherein R2 represents a peptide or protein capable of binding through its own thiol group within the molecule, and R1, R3, R4, and R5 are the same as defined above; a salt thereof; or a hydrate thereof.
4) A cyclooxygenase-2-inhibitor containing, as an active ingredient, S-(2-phenylcarbamoyl-phenylselenyl)-albumin (hereinafter referred to as compound B), a salt thereof, or a hydrate thereof.
The present invention is further directed to a method for producing a pharmaceutical composition for the therapy and/or prophylaxis of such diseases which are caused in a disturbance and/or in an influence of the cyclooxygenase-2-inhibition wherein for producing of said composition a cyclooxygenase-2-inhibitor is used as active ingredient, wherein said cyclooxygenase-2-inhibitor is characterized by the before described general formulas.
Moreover the present invention is preferably directed to a method for producing a pharmaceutical composition for the therapy and/or prophylaxis of ischemic diseases, senile dementia, cancer, asthma, arterial sclerosis, and/or inflammation diseases wherein for producing of said composition a cyclooxygenase-2-inhibitor of the afore mentioned type is used as active ingredient.
In the frame of the present invention the term active ingredient is not only used for a single active ingredient but also for a mixture of active ingredients, which are used for the producing of the inventive composition accordingly.
Furthermore the present invention is directed to a method for therapy and/or prophylaxis of such diseases which are caused in a disturbance and/or in an influence of the cyclooxygenase-2-inhibition, wherein a pharmaceutical composition comprising a cyclooxygenase-2-inhibitor according to the afore described type as active ingredient is orally administered in a daily dosage of 100 to 2000 mg, relative to the active ingredient, for an adult.
Perferably a composition is orally administered to an adult having such a concentration of said active ingredient that a daily dosage of 200 to 1000 mg is given.
If the inventive method is used for therapy and/or prophylaxis of such diseases which are caused in a disturbance and/or in an influence of the cyclooxygenase-2-inhibition a pharmaceutical composition comprising a cyclooxygenase-2-inhibitor as active ingredient is perorally administered in a daily dosage of 0.05 to 1000 mg, relative to the active ingredient, for an adult.
Preferably the inventive method is used for therapy and/or prophylaxis of ischemic diseases, senile dementia, cancer, asthma, arterial sclerosis, and/or inflammation diseases.
Depending on the concentration of the active ingredient which is to administer the inventive composition is given one time to three times each day.